bims-moremu 2025-09-14 papers

bims-moremu

Biomed News

on Molecular regulators of muscle mass

Issue of 2025–09–14
34 papers selected by
Anna Vainshtein, Craft Science Inc.

Muscle Memory of Exercise Optimizes Mitochondrial Metabolism to Support Skeletal Muscle Growth.
The Effect of Cachexia on the Feeding Regulation of Skeletal Muscle Protein Synthesis in Tumour-Bearing Mice.
O-GlcNAcase Inhibitor Improves Denervation-Induced Muscle Atrophy in Mice.
Voluntary Wheel Running Mitigates Disease in an Orai1 Gain-of-Function Mouse Model of Tubular Aggregate Myopathy.
ACSS2 involved in acetyl-CoA synthesis regulates skeletal muscle function.
Early Regulation and Alternative Splicing Dynamics in Glucocorticoid Muscle Atrophy Revealed by Temporal Omics in C2C12 Myotubes.
Defective mitochondrial quality control in the aging of skeletal muscle.
Episodic denervation as a driver of loss of skeletal muscle redox homeostasis and muscle weakness in sarcopenia: Possible amelioration by exercise.
Combined effects of mechanical overload and high-intensity interval training on skeletal muscle hypertrophy in male mice.
Pro-Fibrotic Immune Cells and Fibro-Adipogenic Progenitors Contribute to Skeletal Muscle Extracellular Matrix Remodeling and Fibrosis in Cancer Cachexia.
Vasoconstrictor responsiveness in resting and contracting skeletal muscle following an acute bout of exercise: Impact of aging.
Molecular Pathogenesis of Sarcopenia: Regulatory Networks Involving MicroRNAs in Age-Related Skeletal Muscle Decline.
Increasing indices of frailty in aged female mice are associated with impaired skeletal muscle resilience to downhill running stress.
Electrical pulse stimulation reflecting the episodic nature of real-life exercise modulates metabolic and secretory profile of primary human myotubes.
Unraveling the matrisome signatures of quiescent and activated muscle stem cells.
The impact of Hnrnpl deficiency on transcriptional patterns of developing muscle cells.
Extracellular Vesicle-Mediated miR-155 from Visceral Adipocytes Induces Skeletal Muscle Dysplasia in Obesity.
Integrative physiology of skeletal muscle for maintaining cognitive health.
Exercise as a Therapy for Successful Aging.
Short term daily deflazacort decreases membrane permeability and increases maximum force in mdx mice.
Biglycan Alleviates Age-Related Muscle Atrophy and Hepatocellular Senescence.
Epigenetic small molecule screening identifies a new HDACi compound for ameliorating Duchenne muscular dystrophy.
Macrophage metabolic rewiring rejuvenates muscle raman signatures and cellular remodeling during regrowth in aged mice.
Skeletal Muscle Alpha Actin (ACTA1) Acetylation Enhances Myosin Binding and Increases Calcium Sensitivity.
A myotropic AAV vector combined with skeletal muscle cis-regulatory elements improve glycogen clearance in mouse models of Pompe disease.
Valproic acid-based self-assembling nanoparticle prodrugs prevent skeletal muscle loss in cancer cachexia.
Assessment of different preservation techniques for human skeletal muscle biopsy samples: A comparative method study on freeze-drying, RNAlater, and RNAlater-ICE.
Molecular subtypes of human skeletal muscle in cancer cachexia.
H-silicene nanosheets as a novel therapeutic approach for disuse muscle atrophy by modulating macrophage polarization.
Muscle Biomarkers as Molecular Signatures for Early Detection and Monitoring of Muscle Health in Aging.
Urolithin a modulates inter-organellar communication via calcium-dependent mitophagy to promote healthy ageing.
A novel information theoretic approach reveals loss of effective biomolecular communication in aging muscle cells.
Clock Gene Expression Modulation by Low- and High-Intensity Exercise Regimens in Aging Mice.
CL316,243 and Skeletal Muscle Metabolism: Role of Sex and Estrogen Receptor Beta.

Am J Physiol Cell Physiol. 2025 Sep 12.

Muscle Memory of Exercise Optimizes Mitochondrial Metabolism to Support Skeletal Muscle Growth.

Clay J Weidenhamer, Yi-Heng Huang, Subhashis Natua, Auinash Kalsotra, Diego Hernandez-Saavedra.

  Exercise protects against age-related declines in skeletal muscle mass and function while improving overall health. Exercise can also prime long-term muscle health to enhance adaptations upon exercise retraining, a phenomenon termed muscle memory that remains largely understudied. To assess how prior endurance training elicits a lasting metabolic memory in skeletal muscle, we utilized C57BL/6 mice fed either a control (CD) or obesogenic diet (HFD) that underwent 4-week training, detraining, and retraining periods. Our results show that exercise retraining attenuated weight gain and potentiated muscle growth, even with reduced voluntary running volumes. Training increased fiber size (fCSA), which disappeared with detraining and was recovered with retraining regardless of diet, pointing to a glycolytic-to-oxidative fiber shift. Transcriptomic analysis (bulk RNA-seq) of the retrained muscle revealed a robust enhancement of mitochondrial oxidative phosphorylation (OxPhos) and mitoribosomal genes, paralleled by increases in OxPhos protein complex IV levels, higher long-chain fatty acid oxidative capacity (ACADL), and sustained citrate synthase activity 1 week after retraining, reinforcing the optimization of mitochondrial metabolism. While transcriptomic evidence revealed a major overlap between HFD- and CD-fed mice, discrepancies in protein abundance emerged, which point to an intricate regulation of mitochondrial programming that supports the muscle memory of growth. Our study identifies common and selective mechanisms by which the muscle memory of exercise overrides dietary challenges and promotes fiber hypertrophy, offering insight into potential mechanisms to leverage to promote healthy aging.

Keywords:  Exercise; Hypertrophy; Mitochondria; Muscle Memory; Skeletal Muscle

DOI:  https://doi.org/10.1152/ajpcell.00451.2025
J Cachexia Sarcopenia Muscle. 2025 ;16(5): e70064

The Effect of Cachexia on the Feeding Regulation of Skeletal Muscle Protein Synthesis in Tumour-Bearing Mice.

Brittany R Counts, Quan Zhang, Jessica L Halle, Melissa J Puppa, Stephen E Alway, Junaith Mohamed, Jeremy P Loenneke, James A Carson.

   BACKGROUND: Cancer promotes muscle wasting through an imbalance in the tightly regulated protein synthesis and degradation processes. An array of intracellular signalling pathways, including mTORC1 and AMPK, regulate protein synthesis, and these pathways are responsive to the muscle's microenvironment and systemic stimuli. Although feeding and fasting are established systemic regulators of muscle mTORC1 and protein synthesis, the cancer environment's impact on these responses during cachexia development is poorly understood. Although the IL-6 cytokine family has been widely investigated as a driver of cachexia with several cancers, how this signalling regulates muscle responses to feeding and fasting requires further study. We investigated if the cancer environment alters the feeding and fasting regulation of skeletal muscle protein synthesis and if the IL-6 family of cytokines signalling through muscle glycoprotein 130 could regulate this response.
METHODS: Male C57BL/6J mice were subcutaneously injected with 1 × 106 LLC cells or PBS. Mice were euthanized 25-30 days post-injection after a 12-h dark cycle fast, followed by access to food pellets for 1 h (fed) or immediately sacrificed. To determine AMPK and gp13's regulation of protein synthesis and anabolic signalling, we injected tamoxifen-inducible skeletal muscle AMPKa1a2 or gp130 knockout and floxed control mice with LLC cells or PBS. The gastrocnemius muscle was analysed for protein expression.
RESULTS: Feeding increased p-rpS6 and protein synthesis in PBS (2.2- and 0.4-fold, p < 0.001) and LLC mice (1.7- and 0.9-fold, p < 0.001), but overall, LLC significantly reduced p-rpS6 and protein synthesis. Feeding only increased p-AKT in PBS mice (1.5-fold, p < 0.001). In vitro LLC-conditioned media did not inhibit the insulin induction of myotube p-AKT (p < 0.001) and p-rpS6 (p < 0.001). Muscle gp130 loss reduced the fasting p-AMPK induction in LLC mice but did not alter suppression of p-AKT and p-rpS6 and protein synthesis. Muscle AMPK loss increased p-rpS6 (2.1-fold, p < 0.001) and protein synthesis (0.7-fold, p < 0.001) in PBS mice but did not restore LLC-suppressed protein synthesis.
CONCLUSIONS: Our study provides novel insight into muscle responsiveness to feeding and fasting in a cancer environment. We find the acute anabolic response to feeding is maintained during LLC-induced cachexia, whereas the fasting catabolic response is exacerbated. Muscle-specific gp130 loss prevented disrupted fasting AMPK activation but not protein synthesis. There is a need to understand the aberrant upstream and downstream regulation of muscle AMPK activity that is disrupted with cancer and leads to aberrant protein turnover regulation.

Keywords:  anabolism; cancer; fasting; feeding; inflammation

DOI:  https://doi.org/10.1002/jcsm.70064
J Cachexia Sarcopenia Muscle. 2025 Oct;16(5): e70066

O-GlcNAcase Inhibitor Improves Denervation-Induced Muscle Atrophy in Mice.

Tomoyasu Suenaga, Shouji Matsushima, Tomoka Masunaga, Toru Hashimoto, Shingo Takada, Yoshizuki Fumoto, Soichiro Hata, Kohtaro Abe, Shintaro Kinugawa.

   BACKGROUND: Skeletal muscle atrophy occurs in various situations, such as denervation, fasting and ageing. Disruption of the balance between protein synthesis and degradation plays an important role in muscle atrophy, and impaired Akt phosphorylation is considered to be crucial in this process. The attachment of an O-linked N-acetylglucosamine motif (O-GlcNAcylation), which is a post-translational modification mediated by the hexosamine biosynthetic pathway, an alternative pathway of glycolysis, is involved in the regulation of protein function. Akt O-GlcNAcylation interacts with Akt phosphorylation, thereby regulating its function. The purpose of this study was to clarify the role of O-GlcNAcylation in skeletal muscle atrophy and to identify a therapeutic target for its prevention.
METHODS: Denervation was induced by cutting the sciatic nerve on the right leg of male C57BL/6J mice. A sham operation was performed on the left leg. Three days after the operation, the mice were divided into two groups: One group was treated with the O-GlcNAcase inhibitor thiamet G (1 mg/kg body weight/day), and the other group was treated with vehicle. Seven days after the operation, the gastrocnemius muscle was collected and analysed. The effect of adeno-associated virus serotype 1-mediated suppression of O-GlcNAcase on skeletal muscle atrophy was also investigated. Finally, in C2C12 myotubes with adenovirus-mediated overexpression of wild-type Akt and O-GlcNAcylation-resistant mutant Akt (T479A), the interaction between the phosphorylation and O-GlcNAcylation of Akt was investigated.
RESULTS: The weight of denervated gastrocnemius muscle was decreased by 35.6% (p < 0.05) compared with sham. Akt phosphorylation was decreased by 27.8% (p < 0.05), and the expression of the muscle-specific ubiquitin ligases muscle atrophy F-box (atrogin-1) and muscle RING Finger-1 (MuRF1) was increased in denervated muscle compared with sham. Akt O-GlcNAcylation was decreased in denervated muscle compared with sham by 45.3% (p < 0.05), together with an 8.9-fold increase in O-GlcNAcase expression. Thiamet G reduced gastrocnemius muscle weight loss by 22.7% (p < 0.05) compared with vehicle, and this was achieved through an increase in Akt phosphorylation by 63.5% (p < 0.05) and decreases in atrogin-1 and MuRF1 expression. The inhibition of O-GlcNAcase by gene silencing also improved skeletal muscle atrophy. The overexpression of mutant Akt (T479A) showed less O-GlcNAcase inhibition-induced Akt phosphorylation than the overexpression of wild-type Akt.
CONCLUSIONS: O-GlcNAcase inhibition improved denervation-induced skeletal muscle atrophy in mice by increasing Akt O-GlcNAcylation. O-GlcNAcase may hence be a therapeutic target for preventing skeletal muscle atrophy.

Keywords:  O‐GlcNAcase; O‐GlcNAcylation; denervation‐induced muscle atrophy; phosphorylation; skeletal muscle; thiamet G

DOI:  https://doi.org/10.1002/jcsm.70066
Cells. 2025 Sep 04. pii: 1383. [Epub ahead of print]14(17):

Voluntary Wheel Running Mitigates Disease in an Orai1 Gain-of-Function Mouse Model of Tubular Aggregate Myopathy.

Thomas N O'Connor, Nan Zhao, Haley M Orciuoli, Sundeep Malik, Alice Brasile, Laura Pietrangelo, Miao He, Linda Groom, Jennifer Leigh, Zahra Mahamed, Chen Liang, Feliciano Protasi, Robert T Dirksen.

  Tubular aggregate myopathy (TAM) is an inherited skeletal muscle disease associated with progressive muscle weakness, cramps, and myalgia. Tubular aggregates (TAs) are regular arrays of highly ordered and densely packed straight-tubules observed in muscle biopsies; the extensive presence of TAs represent a key histopathological hallmark of this disease in TAM patients. TAM is caused by gain-of-function mutations in proteins that coordinate store-operated Ca2+ entry (SOCE): STIM1 Ca2+ sensor proteins in the sarcoplasmic reticulum (SR) and Ca2+-permeable ORAI1 channels in the surface membrane. Here, we assessed the therapeutic potential of endurance exercise in the form of voluntary wheel running (VWR) in mitigating TAs and muscle weakness in Orai1G100S/+ (GS) mice harboring a gain-of-function mutation in the ORAI1 pore. Six months of VWR exercise significantly increased specific force production, upregulated biosynthetic and protein translation pathways, and normalized both mitochondrial protein expression and morphology in the soleus of GS mice. VWR also restored Ca2+ store content, reduced the incidence of TAs, and normalized pathways involving the formation of supramolecular complexes in fast twitch muscles of GS mice. In summary, sustained voluntary endurance exercise improved multiple skeletal muscle phenotypes observed in the GS mouse model of TAM.

Keywords:  aggregate; exercise; mitochondria; myopathy; physiology; proteomics; sarcoplasmic reticulum; skeletal muscle

DOI:  https://doi.org/10.3390/cells14171383
FEBS Lett. 2025 Sep 12.

ACSS2 involved in acetyl-CoA synthesis regulates skeletal muscle function.

Mekala Gunasekaran, Gloriana Campos, Natalya M Wells, Khanhlinh Lambuu, Isabelle Draper, Christina A Pacak, Peter B Kang.

  Acyl-coenzyme A synthetase short-chain family member-2 (ACSS2) catalyzes the conversion of acetate to acetyl-CoA, regulating cholesterol metabolism. Given the discovery of a muscular dystrophy associated with 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR), a key enzyme in cholesterol synthesis, we studied Acss2 in mice and the orthologous gene AcCoA in flies. Skeletal muscle from Acss2-/- mice showed atrophic fibers, lipid accumulation, and depleted NADH levels, while myoblasts from these mice displayed precocious differentiation. Exercise induced fatigue in the Acss2-/- mice, which was accentuated by inhibition of ATP-citrate lyase (ACLY) activity. AcCoA knockdown yielded reduced body sizes and locomotor defects in Drosophila. ACSS2 is vital for skeletal muscle function and merits study as a potential factor in muscle diseases related to cholesterol metabolism. Impact statement ACSS2 catalyzes the conversion of acetate to acetyl-CoA, regulating cholesterol metabolism. Given the increasingly apparent links between cholesterol metabolism and skeletal muscle function, we investigated ACSS2 deficiency in mouse and fly models. We identified defects in muscle morphology, muscle metabolism, and motor function. ACSS2 is vital for skeletal muscle.

Keywords:  ACSS2; cholesterol metabolism; muscle development

DOI:  https://doi.org/10.1002/1873-3468.70152
Am J Physiol Cell Physiol. 2025 Sep 08.

Early Regulation and Alternative Splicing Dynamics in Glucocorticoid Muscle Atrophy Revealed by Temporal Omics in C2C12 Myotubes.

Suzuka Nakagawa, Aristotelis Misios, Oliver Popp, Philipp Mertins, Ernst Jarosch, Jens Fielitz, Thomas Sommer.

  Skeletal muscle atrophy and weakness are major contributors to morbidity, prolonged recovery, and long-term disability across a wide range of diseases. Atrophy is caused by breakdown of sarcomeric proteins resulting in loss of muscle mass and strength. Molecular mechanism underlying the onset of muscle atrophy and its progression have been analysed in patients, mice, and cell culture but the complementarity of these model systems remains to be explored. Here, we applied deep-coverage transcriptomic and proteomic profiling for an updated view on dynamic changes during dexamethasone-induced atrophy in the widely used murine skeletal muscle cell line C2C12. Comparison with published mouse data confirmed that muscle differentiation is well recapitulated in C2C12 myotubes. Under dexamethasone treatment, this model was particularly suited to capture early atrophy events. We additionally identified alterations in mitochondrial gene expression and differential alternative splicing events during early-stage myotube atrophy. This dataset complements existing in vivo data and provides novel insights into the regulatory processes during skeletal muscle wasting.

Keywords:  Alternative splicing; Atrophy; Glucocorticoid; Omics; Skeletal muscle

DOI:  https://doi.org/10.1152/ajpcell.00518.2025
Mech Ageing Dev. 2025 Sep 08. pii: S0047-6374(25)00088-0. [Epub ahead of print]228 112112

Defective mitochondrial quality control in the aging of skeletal muscle.

Emanuele Marzetti, Riccardo Calvani, Helio José Coelho-Junior, Francesco Landi, Anna Picca.

  Age-related skeletal muscle decline is a major contributor to frailty, functional impairment, and loss of independence in advanced age. This process is characterized by selective atrophy of type II fibers, impaired excitation-contraction coupling, and reduced regenerative capacity. Emerging evidence implicates mitochondrial dysfunction as a central mechanism in the disruption of muscle homeostasis with age. Beyond ATP production, mitochondria orchestrate redox signaling, calcium handling, and apoptotic pathways, which are increasingly compromised in aged muscle due to chronic oxidative stress and defective quality control. High-resolution respirometry has revealed intrinsic, lifestyle-independent declines in mitochondrial respiratory capacity, while large-scale phenotyping and transcriptomic profiling have established robust associations between mitochondrial integrity, physical performance, and mobility. These findings have prompted a paradigm shift from static descriptions of mitochondrial decline toward dynamic analyses of mitochondrial signaling networks and stress adaptability. Several quality control mechanisms, including mitochondrial biogenesis, dynamics, mitophagy, and vesicle trafficking, emerge as critical regulators of myocyte integrity. Understanding how these systems deteriorate with age will be pivotal for developing therapeutic targets to preserve muscle function, mitigate sarcopenia, and extend health span.

Keywords:  Autophagy; Damage associated molecular patterns; Mitochondrial DNA; Mitochondrial dynamics; Mitophagy; Myocyte; Proteasome

DOI:  https://doi.org/10.1016/j.mad.2025.112112
Sports Med Health Sci. 2025 Sep;7(5): 341-350

Episodic denervation as a driver of loss of skeletal muscle redox homeostasis and muscle weakness in sarcopenia: Possible amelioration by exercise.

Malcolm J Jackson.

  Substantial reductions in muscle motor unit numbers accompany ageing and occur in parallel the age-related changes in skeletal muscle mass and fibre number. These motor unit changes are reflected in reduced motor neuron numbers and size, axonal integrity and disrupted pre-and post-synaptic neuromuscular junctions (NMJ). Conversely, data indicate that the effects of ageing on neuromuscular transmission are relatively minor. Some authors have therefore argued that structural degeneration of motor axons and NMJ are unimportant in the pathogenesis of sarcopenia and for a non-neurogenic origin for ageing-induced muscle loss. Increased Reactive Oxygen Species (ROS) activities and changes in redox status are a feature of ageing and may play a key role in muscle loss through increased mitochondrial peroxide generation. This article will review the changes in motor units and NMJ seen during ageing and develop the argument that the changes in muscle mitochondrial peroxide generation and redox status may be caused by age-related changes in neuromuscular structure, but are not directly related to neuromuscular transmission. This provides an alternative explanation on how age-related changes in neural tissue might drive skeletal muscle fibre loss and weakness. Exercise interventions are known to reduce muscle loss and weakness in the elderly, but studies of such interventions on age-related changes in motor units, motor neurons or NMJ structure and function provide conflicting data. A further aim is therefore to identify areas where there is a need for novel research to understand whether, and how, targeted or long-term exercise might influence neuromuscular changes in ageing.

Keywords:  Mitochondria; Muscle fibre; Neuromuscular junction; Reactive oxygen species

DOI:  https://doi.org/10.1016/j.smhs.2025.02.002
Physiol Rep. 2025 Sep;13(17): e70542

Combined effects of mechanical overload and high-intensity interval training on skeletal muscle hypertrophy in male mice.

Hayato Shinkai, Takanaga Shirai, Kazuki Uemichi, Ryoto Iwai, Tomohiro Iwata, Riku Tanimura, Shunsuke Sugiyama, Tohru Takemasa.

  Athletes often perform concurrent training that combines different exercise modalities. It is believed that muscle hypertrophic adaptation is inhibited by endurance exercise; however, the molecular mechanisms underlying the effects of high-intensity, short-duration exercise on muscle hypertrophic responses remain unclear. In this study, we determined the effects of high-intensity interval training (HIIT) on mechanical overload-induced muscle hypertrophy in mice. Eight-week-old male mice were divided into the following three groups (n = 6-8): Sham surgery (Sham), myotenectomy-induced mechanical overload (OL), and OL with HIIT by forced swimming (OL + HIIT). After 4 weeks of intervention, the OL + HIIT group exhibited an increase in plantaris muscle weight and muscle fiber cross-sectional area as well as the OL group. The OL + HIIT group showed a similar increase in mTOR downstream proteins rpS6, S6K1, and 4E-BP1 phosphorylation compared with the OL group. AMPK was activated by HIIE and may play an inhibitory role by attenuating mTOR. To clarify its involvement, acute phase experiments were conducted to evaluate mTOR signaling immediately after a single round of HIIE. The increase of rpS6 and S6K1 phosphorylation was unchanged after a single HIIE exposure, despite AMPK upregulation. Our results suggest that interference effects induced by HIIE may not occur in mechanically overloaded mouse skeletal muscle.

Keywords:  high‐intensity interval training; hypertrophy; mTOR signaling; skeletal muscle

DOI:  https://doi.org/10.14814/phy2.70542
Am J Physiol Cell Physiol. 2025 Sep 10.

Pro-Fibrotic Immune Cells and Fibro-Adipogenic Progenitors Contribute to Skeletal Muscle Extracellular Matrix Remodeling and Fibrosis in Cancer Cachexia.

Thomas D Cardaci, Arianna V Bastian, Kasie Roark, Brooke M Bullard, Mitchell M NeSmith, Christian A Unger, Robert L Price, Jason L Kubinak, E Angela Murphy, Brandon N VanderVeen.

  Cachexia, the loss of skeletal muscle mass and function with cancer, contributes to reduced life quality and worsened survival. Skeletal muscle fibrosis leads to disproportionate muscle weakness; however, the role of infiltrating immune cells and fibro-adipogenic progenitors (FAPs) in cancer-induced muscle fibrosis is not well understood. Using the C26 model of cancer cachexia, we sought to examine the changes to skeletal muscle immune cells and FAPs which contribute to excessive extracellular matrix (ECM) collagen deposition. CD2F1 male mice (n=35) were implanted with either 106 C26 or CT-26 (weight stable; WS) cells. Skeletal muscle immune cell populations, satellite cells, and FAPs were examined using high-dimensional flow cytometry. Skeletal muscle ECM ultrastructure was assessed via scanning electron microscopy (SEM) of decellularized muscle along with transmission electron microscopy (TEM). Cachectic mice had significant decreases in body weight (-13.4%, p=0.003) and skeletal muscle mass (-37%, p=0.006). Cachectic mice had elevated CD45+CD11b+Ly6g+ neutrophils compared to non-tumor bearing controls (128%, p=0.016) and elevated CD45+CD11b+Ly6g-F480+CD206+MHCII- profibrotic macrophages and increased CD45-Sca1+CD106+CD140a+ FAPs compared to WS (43%, p=0.014) and controls (59%, p=0.002) with thickening of the ECM, particularly of the endomysium and perimysium. SEM and TEM analysis also identified clusters of infiltrating cells localized to regions of excessive ECM deposition in cachectic mice that were absent in WS and controls. These data highlight changes to the muscle microenvironment which contribute to fibrosis and excessive ECM deposition in cancer cachexia. Targeting pro-fibrotic immune cells may represent a promising therapeutic approach to mitigate muscle wasting and dysfunction with cachexia.

Keywords:  FAPs; atrophy; macrophages; muscle wasting; weakness

DOI:  https://doi.org/10.1152/ajpcell.00448.2025
J Appl Physiol (1985). 2025 Sep 09.

Vasoconstrictor responsiveness in resting and contracting skeletal muscle following an acute bout of exercise: Impact of aging.

DongNyeuck Seo, Jack E Shelley, Erika Iwamoto, Darren P Casey.

  Long-term exercise training can attenuate sympathetic vasoconstriction in both resting and contracting skeletal muscle; however, the impact of an acute bout of exercise on vasoconstrictor responsiveness and the influence of aging is unknown. Therefore, we tested the hypothesis that an acute bout of exercise will blunt sympathetic-mediated vasoconstriction in resting and contracting skeletal muscle of young and older adults. Twenty-one adults (10 Young: 23±5 yr and 11 Older: 65±8 yr) performed a rest and a rhythmic handgrip exercise trial before and after either 30 minutes of cycling exercise (60-65% HRmax) or a time control period (seated rest). Lower body negative pressure (- 30mmHg) was applied during each trial to induce sympathetic-mediated vasoconstriction. Forearm blood flow (FBF; ml/min) was assessed via Doppler ultrasound and forearm vascular conductance (FVC; ml·min-1·100 mmHg-1) was calculated as the quotient of FBF and mean arterial pressure (mmHg). The acute bout of cycling exercise did not change vasoconstrictor responsiveness (% change FVC) in resting skeletal muscle in either age group (P>0.05). However, vasoconstrictor responsiveness was attenuated in contracting skeletal muscle following the acute bout cycling exercise in the group (-11.0 ± 5.7 to -8.2 ± 5.1%, P<0.001), as well as separated by age (Young: -6.7 ± 3.2 to -5.0 ± 4.0%, Older: -14.9 ± 4.6 to -11.0 ± 4.2%, P<0.01 for both). Our data indicate that an acute bout of exercise does not change vasoconstrictor responsiveness in resting skeletal muscle but enhances functional sympatholysis in young and older adults.

Keywords:  acute exercise; aging; blood flow; functional sympatholysis

DOI:  https://doi.org/10.1152/japplphysiol.00549.2025
Front Biosci (Landmark Ed). 2025 Aug 29. 30(8): 38106

Molecular Pathogenesis of Sarcopenia: Regulatory Networks Involving MicroRNAs in Age-Related Skeletal Muscle Decline.

Joseph Joju Kalan, Lijo N Varghese, Rajesh Katare.

  Sarcopenia is the progressive loss of skeletal muscle mass, strength, and function, significantly contributing to frailty, disability, and mortality in aging populations. As life expectancy rises, sarcopenia presents a growing public health challenge, increasing healthcare costs, and diminishing quality of life. Despite its prevalence, sarcopenia is often underdiagnosed due to limitations in current diagnostic tools, including the lack of standardized cut-off values and reliance on physical performance tests. The causes of sarcopenia are multifactorial, involving oxidative stress, chronic inflammation, mitochondrial dysfunction, satellite cell depletion, and impaired angiogenesis. Recent research highlights the role of microRNAs (miRs) in regulating these molecular pathways. miRs influence muscle homeostasis by modulating gene expression related to muscle atrophy, apoptosis, inflammation, and insulin resistance. While non-pharmacological interventions such as resistance training and blood flow restriction therapy remain the primary treatment strategies, their effectiveness is often limited in older adults with reduced muscle regenerative capacity. The identification of miRs as biomarkers could enhance early diagnosis and enable more personalized treatment approaches. However, further research is required to validate their clinical utility and therapeutic potential. This review comprehensively analyses the molecular mechanisms underlying sarcopenia, current diagnostic challenges, and emerging miR-based strategies that could transform its management. Future efforts should focus on integrating these molecular insights into clinical practice to improve early detection and intervention strategies.

Keywords:  aging; microRNAs; molecular mechanisms; muscle; sarcopenia; skeletal

DOI:  https://doi.org/10.31083/FBL38106
Geroscience. 2025 Sep 11.

Increasing indices of frailty in aged female mice are associated with impaired skeletal muscle resilience to downhill running stress.

Grant R Laskin, Laís R Perazza, Ted G Graber, Baylah R Mazonson, Yuhoung J Kim, Laura J Verdi, LaDora V Thompson.

  Frailty is a clinical syndrome marked by diminished physiological reserve and function. While skeletal muscle dysfunction is central to frailty, most preclinical models focus on basal function and place less emphasis on physiological stress responses. Here, we examined the influence of increased indices of frailty on skeletal muscle resistance and resilience using a physiologically relevant model of downhill running stress. Aged female C57BL/6JN mice (n = 47; > 17 months) were stratified into Low (≤ 1 frailty markers) or High (≥ 2 frailty markers) groups based on their number of positive frailty markers. Mice were subsequently randomized to undergo two bouts of downhill running or remain cage sedentary. Twenty-four hours later, contractile function was assessed ex vivo in the extensor digitorum longus (EDL) and soleus muscles. RNA was extracted from the gastrocnemius of randomly selected samples and analyzed by RNA sequencing. Despite comparable specific tetanic force, High frailty marked mice exhibited greater fatiguability and impaired recovery kinetics in the EDL following running stress. RNA sequencing revealed divergent transcriptional signatures between mice in Low and High frailty marked groups in response to running, including upregulation of mitochondrial bioenergetic and complex assembly pathways in Low group mice and downregulation in High group mice. These data demonstrate that downhill running stress unmasks latent impairments with frailty in skeletal muscle, and that mitochondrial dysfunction and/or redox imbalance may be potential contributors to reduced muscle resilience. Overall, our results emphasize the importance of incorporating physiological stress paradigms to uncover frailty-associated muscle impairments that are not apparent under basal conditions.

Keywords:  Frailty; Mitochondrial dysfunction; Muscle contractility; Stress resilience

DOI:  https://doi.org/10.1007/s11357-025-01856-7
FEBS Open Bio. 2025 Sep 09.

Electrical pulse stimulation reflecting the episodic nature of real-life exercise modulates metabolic and secretory profile of primary human myotubes.

Klára Gabrišová, Tímea Kurdiová, Daria Barkova, Natália Pálešová, Jana Babulicová, Silvia Tyčiaková, Marta Novotová, Mária Balážová, Miroslav Sabo, Václav Pustka, Jozef Ukropec, Barbara Ukropcová.

  Electrical pulse stimulation (EPS) represents a useful tool to study exercise-related adaptations of muscle cells in vitro. Here, we examine the metabolic and secretory response of primary human muscle cells from metabolically healthy individuals to the EPS protocol reflecting the episodic nature of real-life exercise training. This intermittent EPS protocol alternates high-frequency stimulation periods with low-frequency resting periods. Continuous EPS was used as a comparator. Radiometric assessment of glucose and fatty acid metabolism was complemented by examination of mitochondrial OxPHOS proteins, fiber-type markers, and the release of selected myokines and extracellular vesicles into the media. Both EPS protocols facilitated glycogen synthesis and incomplete fatty acid oxidation (intermediary metabolites accumulation), while complete glucose and fatty acid oxidation (CO2 production) was increased only after the intermittent stimulation. Continuous stimulation elicited robust release of the contraction-regulated myokines (IL6, IL8) into the media. Both EPS protocols increased expression of oxidative fiber-type markers (MYH2, MYH7), while inducing protein expression of a putative myokine, growth differentiation factor11 (GDF11) and a release of extracellular vesicles into the media. In conclusion, intermittent electrical pulse stimulation enhanced the rate of complete glucose and fatty acid oxidation in differentiated muscle cells from metabolically healthy individuals, while it was comparable to continuous stimulation in modulating markers of oxidative fibers and a putative myokine GDF11, and less effective in stimulating the release of myokines IL6, IL8, and extracellular vesicles into the media. Intermittent EPS-a protocol mimicking the episodic nature of exercise-can be used for studying metabolism and the secretome of skeletal muscle cells in vitro.

Keywords:  electrical pulse stimulation; extracellular vesicles; glucose and fatty acid metabolism; growth differentiation factor 11; human primary muscle cell culture; myokines

DOI:  https://doi.org/10.1002/2211-5463.70114
Stem Cell Reports. 2025 Sep 11. pii: S2213-6711(25)00239-5. [Epub ahead of print] 102635

Unraveling the matrisome signatures of quiescent and activated muscle stem cells.

Emilie Guillon, Hisoilat Bacar, Laurent Gilquin, Takako Sasaki, Philippos Mourikis, Florence Ruggiero.

  The extracellular matrix (ECM) forms a dynamic microenvironment, known as the "niche," that influences muscle stem cell (MuSC) behavior. Its composition and topology remain underexplored. Using bioinformatics analysis of publicly available transcriptomic data, we profiled the matrisome of skeletal muscle-resident cells and identified quiescent MuSCs as key ECM producers. Their matrisome includes novel markers such as the basement membrane zone genes Col19a1 and Lama3, ECM assembly regulators Thsd4 and Aebp1, and notably, matrisome genes linked to neurogenesis. Light-sheet immunofluorescence microscopy of selected ECM components in isolated murine myofiber bundles revealed niche-specific ECM components associated with MuSCs. Upon activation, these cells shifted their gene expression, downregulating niche-associated ECM genes while upregulating those involved in basement membrane disruption and cell motility. These findings identify distinct matrisome signatures in quiescent and activated MuSCs, emphasizing the critical role of ECM in locally regulating MuSC states and highlighting its therapeutic potential for muscle regeneration.

Keywords:  bioinformatics; extracellular matrix; matrisome; muscle stem cells; quantitative image analysis; stem cell niche

DOI:  https://doi.org/10.1016/j.stemcr.2025.102635
FEBS Open Bio. 2025 Sep 13.

The impact of Hnrnpl deficiency on transcriptional patterns of developing muscle cells.

Hannah R Littel, Mekala Gunasekaran, Audrey L Daugherty, Natalya M Wells, Johnnie Turner, Christine C Bruels, Christina A Pacak, Isabelle Draper, Peter B Kang.

  Heterogeneous nuclear ribonucleoproteins (hnRNPs) bind to RNA, regulating gene expression and splicing. HnRNP L contributes to muscle development and the pathogenesis of myotonic dystrophy. We hypothesized that hnRNP L regulates muscle expression and splicing patterns. Using nanopore long-read transcriptome sequencing and qPCR analyses, we investigated the impact of Hnrnpl knockdown on myoblasts and knockdown of the orthologous gene smooth in Drosophila. Notch signaling genes and muscle-related genes were dysregulated in both models. Several genes had altered splicing patterns, including Lamp2, Fhl1, and Dtna. The α-DB1 isoform of Dtna was downregulated, whereas the α-DB3 isoform was upregulated. Our findings indicate that hnRNP L regulates both the transcription levels and splicing patterns of genes relevant to skeletal muscle development. We demonstrate the capabilities of long-read transcriptome sequencing to study muscle development. Comparisons between nanopore long-read transcriptome sequencing and data from PCR and qPCR analyses suggest that a minimum read depth of 10 is needed on nanopore sequencing to detect splicing differences greater than 10% to 20%. Future studies could determine whether the minimum read depth that we identified in our model is valid across a broader range of genes, cell types, and conditions. There are also intriguing hints of therapeutic implications of hnRNP L regulation for muscle diseases that merit further investigation.

Keywords:  HnRNP L; RNA sequencing; nanopore transcriptomics; skeletal muscle; splicing regulation

DOI:  https://doi.org/10.1002/2211-5463.70117
Cells. 2025 Aug 22. pii: 1302. [Epub ahead of print]14(17):

Extracellular Vesicle-Mediated miR-155 from Visceral Adipocytes Induces Skeletal Muscle Dysplasia in Obesity.

Yunyan Ji, Zeen Gong, Rui Liang, Di Wu, Wen Sun, Xiaomao Luo, Yi Yan, Jiayin Lu, Juan Wang, Haidong Wang.

  Obesity poses a serious threat to human health, with induced skeletal muscle dysfunction significantly increasing the risk of metabolic syndrome. In obesity, it is known that visceral adipose tissue (VAT) mediates the dysregulation of the adipose-muscle axis through exosome-delivered miRNAs, but the associated regulatory mechanisms remain incompletely elucidated. This study established an AAV-mediated miR-155 obese mouse model and a co-culture system (HFD VAD-evs/RAW264.7 cells/C2C12 cells) to demonstrate that high-fat diet-induced VA-derived extracellular vesicles (HFD VAD-evs) preferentially accumulate in skeletal muscle and induce developmental impairment. HFD VAD-evs disrupt skeletal muscle homeostasis through dual mechanisms: the direct suppression of myoblast development via exosomal miR-155 cargo and the indirect inhibition of myogenesis through macrophage-mediated inflammatory responses in skeletal muscle. Notably, miR-155 inhibition in HFD VAD-evs reversed obesity-associated myogenic deficits. These findings provide novel mechanistic insights into obesity-induced skeletal muscle dysregulation and facilitate potential therapeutic strategies targeting exosomal miRNA signaling.

Keywords:  extracellular vesicle; macrophage; miR-155; obesity; skeletal muscle

DOI:  https://doi.org/10.3390/cells14171302
J Physiol. 2025 Sep 07.

Integrative physiology of skeletal muscle for maintaining cognitive health.

Matthew H Brisendine, Joshua C Drake.

  Cognitive decline and physical impairment are often linked with ageing, contributing to declines in health span and loss of independence in older adults. Pathological cognitive decline with age is largely considered to be a brain-centric challenge. However, recent findings have begun to challenge this paradigm as the health of peripheral systems, namely skeletal muscle, predict cognitive decline associated with Alzheimer's disease (AD). Loss of muscle strength (dynapenia), loss of muscle mass (sarcopenia) and associated impairment in peripheral motor nerves and neuromuscular junctions have all been shown to either precede or coincide with AD pathology in the brain. The importance for skeletal muscle is also demonstrated in its role as an endocrine organ, secreting factors like brain-derived neurotrophic factor that promote neurogenesis in the brain. In this review we summarize the importance of skeletal muscle for cognition and discuss how the health of skeletal muscle and peripheral motor nerves may be novel sentinels for AD risk.

Keywords:  Alzheimer's disease; ageing; cognition; motor neuron; neuromuscular junctions; skeletal muscle

DOI:  https://doi.org/10.1113/JP286748
Scand J Med Sci Sports. 2025 Sep;35(9): e70133

Exercise as a Therapy for Successful Aging.

Ignacio Ara, Maria Carmen Gómez-Cabrera, Nuria Garatachea.

  Regular physical activity has profound and multifaceted benefits for individuals as they age. This review highlights the role of exercise in promoting healthy and successful aging, emphasizing its effectiveness in the prevention and treatment of frailty and disability. Exercise is a primary intervention to attenuate the age-related biological and functional decline by targeting mainly the cardiorespiratory, vascular, nervous, and skeletal muscle systems. From a biological perspective, we review the evidence on the role of exercise in mitigating the three categories of the biological hallmarks of aging: primary, antagonistic, and integrative. Different types of exercise may elicit different benefits for older adults. Thus, our review also emphasizes the importance of incorporating tailored and personalized exercise programs that align with individual health profiles and conditions, ranging from geriatric care to senior athletes. We also review the benefits that multicomponent exercise interventions, that combine power-oriented resistance training with high-intensity interval training, have for improving health outcomes in older adults. Overcoming the barriers that deter older adults from exercising requires a comprehensive approach that addresses psychological, economic, social, environmental, and gender perspective factors to increase participation. Governments play a key role by applying evidence-based strategies, offering accessible exercise programs, creating supportive environments, and promoting policies that strengthen older adults' motivation and autonomy. These measures should ensure that all older adults have the same opportunities to engage in exercise, ultimately fostering healthier societies.

Keywords:  frailty; longevity; older people; personalized exercise; sarcopenia; well‐being

DOI:  https://doi.org/10.1111/sms.70133
Am J Physiol Cell Physiol. 2025 Sep 12.

Short term daily deflazacort decreases membrane permeability and increases maximum force in mdx mice.

Kristen D Turner, Ying Qian, Dennis R Claflin, Breanne L Newell-Stamper, Angela K Peter, Daniel E Michele, Alan J Russell, Susan V Brooks.

  Duchenne muscular dystrophy (DMD) is a severe genetic disorder caused by the absence of dystrophin, which leads to mechanical instability of the muscle fiber membrane and a predisposition for cell membrane permeability and contraction-induced muscle injury. Deflazacort is an FDA-approved corticosteroid for treating DMD, and treatment of dystrophic mice with deflazacort reduces inflammation and improves muscle regeneration. Whether deflazacort protects from contraction-induced injury in mdx mice is unknown. To address this question, adult mdx mice were administered 1.2 mg/kg deflazacort daily by oral gavage for either 3 or 8-9 weeks and compared to both vehicle-treated mdx mice and wildtype controls for various measures of susceptibility to injury. Both 3 and 8-9 weeks of deflazacort treatment decreased Evans Blue dye (EBD) accumulation in vivo compared to vehicle-treated controls, but the reduction was substantially greater (58% vs. 26%) following shorter-term treatment. Furthermore, for dorsiflexor muscles evaluated in situ, 3 weeks deflazacort treatment dramatically increased isometric force production, and the force decline induced by a single lengthening contraction was reduced more than 50% compared with vehicle-treated controls. Using ex vivo lumbrical muscle preparations, we found that levels of inter-contraction calcium accumulation significantly correlated with force decline during repeated isometric contractions in all deflazacort-treated mice, and a trend for lower aberrant calcium accumulation was seen following 3 weeks of treatment. Given that some protective effects were reduced or not present in a preclinical model of DMD with longer term steroid treatment, these data provide important evidence for beneficial use of short-term deflazacort.

Keywords:  deflazacort; glucocorticoids; muscular dystrophy; skeletal muscle

DOI:  https://doi.org/10.1152/ajpcell.00187.2025
Int J Mol Sci. 2025 Aug 26. pii: 8286. [Epub ahead of print]26(17):

Biglycan Alleviates Age-Related Muscle Atrophy and Hepatocellular Senescence.

Da Som Lee, Joo Hyun Lim, Yoo Jeong Lee.

  Myokines are secreted by muscle and play crucial roles in muscle repair and regeneration and also impact diverse physiological effects through crosstalk with other metabolic organs. However, aging is associated with a progressive decline in muscle mass, which in turn leads to reduced myokine secretion. This decline may contribute to the development of sarcopenia, leading to an increased risk of metabolic disorders such as type 2 diabetes. Accordingly, interest in identifying novel myokines and elucidating their biological functions is increasing. In this study, we explored the function of biglycan (BGN), a novel myokine, in aging-related metabolic tissues. BGN levels decreased in the muscle tissue and plasma of older adults and aged mice, whereas exercise intervention restored BGN expression in aged mice. BGN counteracted the expression of atrophy-related genes involved in muscle degradation and mitigated muscle mass loss by regulating AKT/mTOR signaling pathway. Notably, BGN decreased the expression of the senescence marker p21 and senescence-associated secretory phenotype (SASP)-related genes in hepatocytes. Additionally, BGN attenuated senescence-induced lipid accumulation and ROS generation. Our results suggest that BGN has beneficial effects against muscle atrophy and hepatocellular senescence, indicating its potential as a protective factor for age-related diseases.

Keywords:  BGN; biglycan; exercise; muscle atrophy; myokine; older adults; senescence

DOI:  https://doi.org/10.3390/ijms26178286
Mol Ther Nucleic Acids. 2025 Sep 09. 36(3): 102683

Epigenetic small molecule screening identifies a new HDACi compound for ameliorating Duchenne muscular dystrophy.

Ke'ale W Louie, Eva H Hasegawa, Gist H Farr, Amanda C Ignacz, Alison Paguio, Alyssa Maenza, Alison G Paquette, Clarissa A Henry, Lisa Maves.

  Duchenne muscular dystrophy (DMD) is the most common inherited muscle disease. There are currently few effective therapies to treat the disease, although many approaches are being pursued. Certain histone deacetylase inhibitors (HDACi) have been shown to ameliorate DMD phenotypes in mouse and zebrafish models, and the HDACi givinostat has recently gained FDA approval for DMD. Our goal was to identify additional HDACi, or other classes of epigenetic small molecules, that are beneficial for DMD. Using an established animal model for DMD, the zebrafish dmd mutant strain sapje, we screened a library of over 800 epigenetic small molecules. Our screening identified a new HDACi, SR-4370, that ameliorated dmd mutant zebrafish skeletal muscle degeneration, as well as additional HDACi that have previously been shown to improve dmd zebrafish. We find that a single early treatment of HDACi can ameliorate the muscle phenotype and increase lifespan in dmd zebrafish. Furthermore, we find that HDACi treatments that improve dmd muscle also cause increased histone acetylation in zebrafish larvae. Our results add to the growing evidence that HDACi are promising candidates for treating DMD. Our study also provides further support for the effectiveness of small molecule screening in dmd zebrafish.

Keywords:  Duchenne muscular dystrophy; HDAC inhibitor; MT: Clinical Applications; drug screen; epigenetic therapy; zebrafish

DOI:  https://doi.org/10.1016/j.omtn.2025.102683
JCI Insight. 2025 Sep 09. pii: e194303. [Epub ahead of print]

Macrophage metabolic rewiring rejuvenates muscle raman signatures and cellular remodeling during regrowth in aged mice.

Zachary J Fennel, Negar Kosari, Paul-Emile Bourrant, Elena M Yee, Robert J Castro, Anu S Kurian, Jonathan Palmer, Morgan Christensen, Katsuhiko Funai, Ryan M O'Connell, Anhong Zhou, Micah J Drummond.

  Impaired muscle regrowth in aging is underpinned by reduced pro-inflammatory macrophage function and subsequently impaired muscle cellular remodeling. Macrophage phenotype is metabolically controlled through TCA intermediate accumulation and activation of HIF1A. We hypothesized that transient hypoxia following disuse in old mice would enhance macrophage metabolic inflammatory function thereby improving muscle cellular remodeling and recovery. Old (20 months) and young adult mice (4 months) were exposed to acute (24h) normobaric hypoxia immediately following 14-days of hindlimb unloading and assessed during early re-ambulation (4- and 7-days) compared to age-matched controls. Treated aged mice had improved pro-inflammatory macrophage profiles, muscle cellular remodeling, and functional muscle recovery to the levels of young control mice. Likewise, young adult mice had enhanced muscle remodeling and functional recovery when treated with acute hypoxia. Treatment in aged mice restored the muscle molecular fingerprint and biochemical spectral patterns (Raman Spectroscopy) observed in young mice and strongly correlated to improved collagen remodeling. Finally, intramuscular delivery of hypoxia-treated macrophages recapitulated the muscle remodeling and recovery effects of whole-body hypoxic exposure in old mice. These results emphasize the role of pro-inflammatory macrophages during muscle regrowth in aging and highlight immunometabolic approaches as a route to improve muscle cellular dynamics and regrowth.

Keywords:  Aging; Fibrosis; Immunotherapy; Macrophages; Metabolism; Muscle biology

DOI:  https://doi.org/10.1172/jci.insight.194303
Biophys Rep (N Y). 2025 Sep 05. pii: S2667-0747(25)00031-X. [Epub ahead of print] 100226

Skeletal Muscle Alpha Actin (ACTA1) Acetylation Enhances Myosin Binding and Increases Calcium Sensitivity.

Samantha S Romanick, Luis Godoy, Adrian Lopez, Allison Matsumura, Kiana Boc, Travis J Stewart, Josh E Baker, Bradley S Ferguson.

Skeletal muscle alpha actin (ACTA1) is important for muscle contraction and relaxation, with historical studies focused on ACTA1 mutations in muscle dysfunction. Proteomics reports have consistently observed that actin, including ACTA1, is acetylated at multiple lysine sites. However, few reports have studied the effects of actin acetylation on cellular function, and fewer have examined ACTA1 acetylation on skeletal muscle function. Here we aimed to examine how ACTA1 acetylation affected actomyosin interactions by determining actin sliding velocity, myosin binding, and calcium sensitivity. In this study, ACTA1 was chemically acetylated via acetic anhydride (AA) to increasing levels of acetylation: low-level acetylation (using 0.1 mM AA), mid-level acetylation (0.3 mM AA), and high-level acetylation (1 mM AA). We report that ACTA1 acetylation significantly decreased actin sliding velocity and actin filament length. Further analysis showed that ACTA1 acetylation significantly increased calcium sensitivity, with a loss of tropomyosin regulation noted with high-level ACTA1 acetylation. Lastly, ACTA1 acetylation enhanced skeletal myosin half maximal binding to actin. These data highlight acetylation as an additional posttranslational modification, outside of phosphorylation, in the regulation of muscle contraction, and skeletal muscle alpha actin function.

DOI: https://doi.org/10.1016/j.bpr.2025.100226
Mol Ther Methods Clin Dev. 2025 Jun 12. 33(2): 101464

A myotropic AAV vector combined with skeletal muscle cis-regulatory elements improve glycogen clearance in mouse models of Pompe disease.

P Sellier, F Collaud, Y Krimi Benchekroun, V Jimenez, X Leon, N Daniele, Q H Pham, J El Andari, T VandenDriessche, M K Chuah, D Grimm, F Bosch, F Mingozzi, G Ronzitti.

  Pompe disease is a glycogen storage disorder caused by mutations in the acid α-glucosidase (GAA) gene, leading to reduced GAA activity and glycogen accumulation in heart and skeletal muscles. Enzyme replacement therapy with recombinant GAA, the standard of care for Pompe disease, is limited by poor skeletal muscle distribution and immune responses after repeated administrations. The expression of GAA in muscle with adeno-associated virus (AAV) vectors has shown limitations, mainly the low targeting efficiency and immune responses to the transgene. To address these issues, we developed AAV capsids with improved skeletal muscle targeting and reduced off-targeting. These capsids combined with codon optimization, muscle-specific cis-regulatory elements, and a synthetic promoter demonstrated a strong skeletal muscle tropism, reduced liver targeting, and enhanced GAA transgene expression and reduced glycogen accumulation in a Gaa -/- mouse model. However, increased muscle-specific expression led to a robust anti-hGAA immune response. To circumvent this, the AAVMYO2 capsid was tested in immunodeficient Gaa -/- Cd4 -/- mice and compared to AAV9 at different doses. The combination of AAVMYO2 with an optimized transgene expression cassette provided a dose-dependent advantage for glycogen reduction in skeletal muscles of Gaa -/- Cd4 -/- mice. These findings support the potential of muscle-specific AAV gene therapy for Pompe disease at lower doses with greater specificity.

Keywords:  AAV gene therapy; Pompe disease; immune response; liver detargeting; muscle targeting

DOI:  https://doi.org/10.1016/j.omtm.2025.101464
Colloids Surf B Biointerfaces. 2025 Sep 05. pii: S0927-7765(25)00627-7. [Epub ahead of print]257 115120

Valproic acid-based self-assembling nanoparticle prodrugs prevent skeletal muscle loss in cancer cachexia.

Shoki Kamemaru, Yutaka Ikeda, Yukio Nagasaki.

  Cancer cachexia is a multifactorial syndrome characterized by persistent skeletal muscle loss, affecting 80 % of patients with advanced cancer and accounting for 20 % of cancer-related deaths. Despite its prevalence, effective treatment options remain limited due to the side effects and poor pharmacokinetic (PK) profiles of existing therapeutics, including valproic acid (VPA). To overcome these limitations, we developed self-assembling VPA-based nanoparticle prodrugs (abbreviated as NanoVPA), consisting of amphiphilic block copolymers, in which VPA is covalently conjugated via ester linkages. NanoVPA significantly improved the PK profile of VPA by suppressing initial rapid plasma concentration spikes and achieving sustained VPA release, maintaining circulation for up to 48 h and enhancing skeletal muscle accumulation within 10 h post-administration. In vivo, twice-weekly administration of NanoVPA significantly attenuated skeletal muscle loss in a cancer cachexia model by downregulating the expression of atrogin-1, a key muscle-specific ubiquitin ligase involved in proteolysis. These findings highlight the potential of NanoVPA as a novel therapeutic strategy for cancer cachexia, offering improved efficacy and reduced dosing frequency with minimized side effects.

Keywords:  Atrogin-1; Cancer cachexia; Polymeric micelles; Self-assembling nanoparticle prodrugs; Sustained drug release; Valproic acid (VPA)

DOI:  https://doi.org/10.1016/j.colsurfb.2025.115120
Physiol Rep. 2025 Sep;13(17): e70562

Assessment of different preservation techniques for human skeletal muscle biopsy samples: A comparative method study on freeze-drying, RNAlater, and RNAlater-ICE.

Sebastian Edman, Alice Engvall, Tuva Eriksson Viklund, Oscar Horwath, William Apró.

  Human skeletal muscle comprises slow-twitch (type I) and fast-twitch (type II) fibers. Fiber type-specific analyses often require manual isolation of fibers, necessitating effective tissue preservation. While freeze-drying remains the standard, alternative preservation methods such as RNAlater and RNAlater-ICE are increasingly used. Besides their utility in preserving RNA, it needs to be determined whether RNAlater and RNAlater-ICE can be utilized for broader downstream biochemical analyses in skeletal muscle tissue. In this study, we compared freeze-drying to RNAlater and three RNAlater-ICE-based protocols. We observed substantial and consistent alterations in protein content, amino acid levels, and enzyme activity depending on the preservation method. Notably, all RNAlater-ICE protocols abolished citrate synthase activity, and branched-chain amino acid levels were markedly reduced in both RNAlater and RNAlater-ICE-treated samples relative to freeze-dried tissue. Total protein concentration was comparable between freeze-dried and RNAlater-preserved muscle, whereas RNAlater-ICE protocols yielded lower values. After centrifugation, supernatant protein concentration was higher in RNAlater-treated samples, but consistently lowest following RNAlater-ICE treatment. Our results demonstrate the importance of choosing an appropriate preservation method for skeletal muscle prior to downstream biochemical analysis and that care should be taken when using RNAlater and RNAlater-ICE for protein or amino acid analysis.

Keywords:  RNAlater; RNAlater‐ICE; Western blot; enzyme activity; freeze‐drying; glycogen; lyophilization; muscle biopsy; post‐translational modifications

DOI:  https://doi.org/10.14814/phy2.70562
Nature. 2025 Sep 10.

Molecular subtypes of human skeletal muscle in cancer cachexia.

Bhumi J Bhatt, Sunita Ghosh, Vera Mazurak, Aurélien Q Brun, Oliver Bathe, Vickie E Baracos, Sambasivarao Damaraju.

Cancer-associated muscle wasting is associated with poor clinical outcomes1, but its underlying biology is largely uncharted in humans2. Unbiased analysis of the RNAome (coding and non-coding RNAs) with unsupervised clustering using integrative non-negative matrix factorization3 provides a means of identifying distinct molecular subtypes and was applied here to muscle of patients with colorectal or pancreatic cancer. Rectus abdominis biopsies from 84 patients were profiled using high-throughput next-generation sequencing. Integrative non-negative matrix factorization with stringent quality metrics for clustering identified two highly coherent molecular subtypes within muscle of patients with cancer. Patients with subtype 1 (versus subtype 2) showed clinical manifestations of cachexia: high-grade weight loss, low muscle mass, atrophy of type IIA and type IIX muscle fibres, and reduced survival. On the basis of differential expression between the subtypes, we identified biological processes that may contribute to cancer-associated loss of muscle mass and function, including altered posttranscriptional regulation and perturbation of neuronal systems; cytokine storm and cellular immune response; pathways related to extracellular matrix; and metabolic abnormalities spanning xenobiotic metabolism, haemostasis, signal transduction, embryonic and/or pluripotent stem cells, and amino acid metabolism. Differential expression between subtypes indicated the involvement of multiple intertwined higher-order gene regulatory networks, suggesting that network interactions of (hub) long non-coding RNAs, microRNAs and mRNAs could represent targets for future research.

DOI: https://doi.org/10.1038/s41586-025-09502-0
Mater Today Bio. 2025 Oct;34 102217

H-silicene nanosheets as a novel therapeutic approach for disuse muscle atrophy by modulating macrophage polarization.

Lubing Cai, Zhiqiang Zhang, Yangyang Chen, Yuqi Li, Ya-Xuan Zhu, Jiwu Chen, Yaying Sun.

  Disuse muscle atrophy (DMA) is characterized by progressive loss of muscle mass and strength, often accompanied by inflammation and macrophage imbalance. Here, we introduce hydrogenated silicene nanosheets (H-silicene) as a novel nanotherapeutic strategy to mitigate DMA through modulating macrophage polarization. H-silicene exhibited good biocompatibility and sustained hydrogen release. In vitro, H-silicene suppressed LPS-induced M1 macrophage activation while promoting M2 polarization, and alleviated myotube atrophy in co-culture assays. In a murine immobilization model, intramuscular H-silicene administration significantly mitigated muscle wasting, reduced fibrosis, and improved functional outcomes. Immunofluorescence staining confirmed a decrease in iNOS+/TNF-α+ cells and an elevated CD206+/IL-10+ populations in treated muscle. Integrated transcriptomic and proteomic analyses revealed H-silicene-mediated modulation of pathways related to inflammation, oxidative stress, and myogenesis. These findings highlight H-silicene as a promising immunoregulatory nanomaterial for the treatment of disuse-induced muscle atrophy.
Methods: H-silicene nanosheets were synthesized from CaSi2 under argon-protected acid treatment and probe-sonicated to obtain dispersible nanosheets. Cytocompatibility was assessed in RAW264.7 and C2C12 cells. Macrophage polarization was analyzed by flow cytometry, ELISA, and immunofluorescence after LPS stimulation ± H-silicene. Conditioned media were applied to differentiated C2C12 myotubes to assess paracrine effects. In vivo, a mouse hindlimb immobilization model was used to induce DMA. Mice received intramuscular injections of H-silicene (250 ppm). Muscle tissue was analyzed by histology, immunofluorescence, behavioral assays, and RNA-seq and proteomics.
Results: H-silicene exhibited low cytotoxicity and dose-dependently suppressed LPS-induced M1 polarization while enhancing M2 polarization. It reduced proinflammatory cytokines and preserved C2C12 myotube morphology in co-culture models. In vivo, H-silicene improved muscle fiber area, reduced collagen deposition, restored grip strength , and improved rotarod performance in DMA mice. Immunostaining confirmed reduced iNOS+/TNF-α+ and increased CD206+/IL-10+ macrophages. Multi-omics analysis revealed regulation of inflammatory and regenerative signaling, including NF-κB, IL-17, and myoblast differentiation pathways.
Conclusion: This study demonstrates that H-silicene alleviates disuse-induced muscle atrophy by promoting the transition from pro-inflammatory M1 macrophages to anti-inflammatory M2 macrophages and remodeling the local immune microenvironment, making it a promising nanotherapeutic for muscle-wasting disorders.

Keywords:  Disuse muscle atrophy; H-silicene; Inflammation; Macrophage polarization; Nanomaterials; Skeletal muscle

DOI:  https://doi.org/10.1016/j.mtbio.2025.102217
Nutrients. 2025 Aug 26. pii: 2758. [Epub ahead of print]17(17):

Muscle Biomarkers as Molecular Signatures for Early Detection and Monitoring of Muscle Health in Aging.

Morgan LeDrew, Pauneez Sadri, Antonia Peil, Zahra Farahnak.

  Maintaining muscle health is essential for preserving mobility, independence, and quality of life with age. As muscle mass and function decline, the risk of frailty, chronic disease, and disability increases. Sarcopenia, characterized by the progressive loss of muscle mass, strength, and function, is a major contributor to these adverse outcomes in older adults. Early identification and monitoring of sarcopenia are critical for timely intervention to prevent irreversible decline. Muscle biomarkers offer a promising approach for detecting muscle deterioration and guiding treatment strategies. This review explores key biomarkers-including insulin-like growth factor 1 (IGF-1), myostatin, interleukin-6 (IL-6), irisin, interleukin 15 (IL-15), and procollagen type III N-terminal propeptide (P3NP)-that reflect underlying processes such as muscle anabolism, inflammation, metabolism, and remodeling. Alterations in these markers are associated with muscle health status. Furthermore, hormonal status, biological sex, and nutritional factors all modulate biomarker levels, emphasizing the need for personalized assessments. Integrating biomarker analysis into clinical practice has the potential to enhance early diagnosis, inform personalized interventions, and ultimately promote healthy aging by maintaining muscle function and reducing disability risk.

Keywords:  healthy aging; muscle biomarkers; muscle health; myokines; sarcopenia

DOI:  https://doi.org/10.3390/nu17172758
Autophagy. 2025 Sep 13.

Urolithin a modulates inter-organellar communication via calcium-dependent mitophagy to promote healthy ageing.

Antonis Roussos, Katerina Kitopoulou, Fivos Borbolis, Christina Ploumi, Despoina D Gianniou, Zhiquan Li, Haijun He, Eleni Tsakiri, Helena Borland, Ioannis K Kostakis, Martina Samiotaki, Ioannis P Trougakos, Vilhelm A Bohr, Konstantinos Palikaras.

  Mitochondrial dysfunction and impaired mitophagy are hallmarks of aging and age-related pathologies. Disrupted inter-organellar communication among mitochondria, endoplasmic reticulum (ER), and lysosomes, further contributes to cellular dysfunction. While mitophagy has emerged as a promising target for neuroprotection and geroprotection, its potential to restore age-associated defects in organellar crosstalk remains unclear. Here, we show that mitophagy deficiency deregulates the morphology and homeostasis of mitochondria, ER and lysosomes, mirroring age-related alterations. In contrast, urolithin A (UA), a gut-derived metabolite and potent mitophagy inducer, restores inter-organellar communication via calcium signaling, thereby, promoting mitophagy, healthspan and longevity. Our multi-omic analyses reveal that UA reorganizes ER, mitochondrial and lysosomal networks, linking inter-organellar dynamics to mitochondrial quality control. In C. elegans, UA induces calcium release from the ER, enhances lysosomal activity, and drives DRP-1/DNM1L/DRP1-mediated mitochondrial fission, culminating in efficient mitophagy. Calcium chelation abolishes UA-induced mitophagy, blocking its beneficial impact on muscle function and lifespan, underscoring the critical role of calcium signaling in UA's geroprotective effects. Furthermore, UA-induced calcium elevation activates mitochondrial biogenesis via UNC-43/CAMK2D and SKN-1/NFE2L2/Nrf2 pathways, which are both essential for healthspan and lifespan extension. Similarly, in mammalian cells, UA increases intracellular calcium, enhances mitophagy and mitochondrial metabolism, and mitigates stress-induced senescence in a calcium-dependent manner. Our findings uncover a conserved mechanism by which UA-induced mitophagy restores inter-organellar communication, supporting cellular homeostasis and organismal health.

Keywords:  Calcium; ER; cellular senescence; geroprotection; lysosome; mitochondria

DOI:  https://doi.org/10.1080/15548627.2025.2561073
J Gerontol A Biol Sci Med Sci. 2025 Sep 08. pii: glaf195. [Epub ahead of print]

A novel information theoretic approach reveals loss of effective biomolecular communication in aging muscle cells.

Sruthi Sivakumar, Ryan William LeFebre, Giulia Menichetti, Hirotaka Iijima, Andrew Mugler, Fabrisia Ambrosio.

  Maintenance of organismal function requires tightly regulated biomolecular communication. However, with aging, communication deteriorates, thereby disrupting effective information flow. Using information theory applied to skeletal muscle single cell RNA-seq data from young, middle-aged, and aged animals, we quantified the loss of communication efficiency over time. We considered communication channels between transcription factors (TF; 'input message') and corresponding target genes (TG; 'output message'). Mutual information (MI), defined as the information effectively transmitted between TFs and TGs, declined with age. This decline was attributed to escalating biological noise and loss of precision with which TFs regulate TGs (ie, channel capacity). When we ranked TF:TG pairs by MI, pairs associated with fatty acid oxidation displayed the greatest loss of communication with aging, while the system preserved communication between pairs related to RNA synthesis. These data suggest ineffective communication with aging against a backdrop of resource reallocation to support essential cellular functions.

Keywords:  Aging; Communication; Information theory; Skeletal muscle; Transcriptomics

DOI:  https://doi.org/10.1093/gerona/glaf195
Int J Mol Sci. 2025 Sep 08. pii: 8739. [Epub ahead of print]26(17):

Clock Gene Expression Modulation by Low- and High-Intensity Exercise Regimens in Aging Mice.

Matheus Callak Teixeira Vitorino, Hugo de Luca Corrêa, Verusca Najara de Carvalho Cunha, Mariana Saliba de Souza, Herbert Gustavo Simões, Thiago Dos Santos Rosa, Elaine Vieira, Rosângela Vieira de Andrade.

  The circadian rhythm controls the sleep/wake cycle and a wide variety of metabolic and physiological functions. Clock genes regulate it in response to both external and endogenous stimuli, and their expression may change because of aging, leading to an increased risk of health problems. Despite the well-described benefits of physical exercise as a circadian synchronizer, there is a lack of literature regarding the role of chronic exercise intensity in clock gene expression during aging. This article aims to analyze the differential expression of genes that regulate the biological clock under the effects of variable-intensity aerobic swimming training in aging mice, determining whether these exercise regimens interfere with the genomic regulation of the circadian rhythm. For this purpose, the mice were exposed to low- and high-intensity exercise and had their heart and gastrocnemius tissues molecularly analyzed by cDNA synthesis and qPCR to determine the expression levels of the selected genes: Clock, Arntl, Per1, Per2, Cry1, Cry2, and Nr1d1. The results showed that low-intensity exercise, performed at workloads below the anaerobic threshold, significantly changed their expression in the gastrocnemius muscle (p < 0.05), while high-intensity exercise had no statistically significant effects (p > 0.05), with the heart being immune to exercise influence except when it comes to the Per1 gene, for which expression was increased (p = 0.031) by low-intensity exercise. Additionally, both body weight and lactate thresholds had no change during the experiment (p > 0.05), while the maximum supported workload was maintained for high-intensity exercise (p > 0.05) and increased for low-intensity exercise (p < 0.01), with the control group experiencing a decay instead (p < 0.05). Thus, the present study highlights the importance of chronic exercise in modulating clock genes and opens exciting possibilities for circadian medicine, such as improvements in exercise capacity, heart condition, and lipid metabolism for subjects of low-intensity regimens.

Keywords:  chronic exercise; circadian cycle; clock genes; heart; skeletal muscle; swimming

DOI:  https://doi.org/10.3390/ijms26178739
J Endocrinol. 2025 Sep 10. pii: JOE-25-0005. [Epub ahead of print]

CL316,243 and Skeletal Muscle Metabolism: Role of Sex and Estrogen Receptor Beta.

Alan Maloney, Jinseok Lee, Eric D Queathem, Kylie Schaller, Shahad Buckhary, Dennis B Lubahn, Rudy J Valentine, Victoria J Vieira-Potter.

   PURPOSE: CL316,243 (CL), a beta 3 adrenergic receptor (B3-AR) agonist has 'exercise mimetic' effects in adipose tissue (AT). CL may also positively affect skeletal muscle (SM), yet the role of estrogen receptor beta (ERβ) in mediating SM-specific effects of CL is not known. We investigated the effects of CL on SM metabolism, as well as the role played by ERβ.
METHODS: High-fat diet-fed male and female wild-type (WT) and ERβ DBD knockout (KO) mice were administered CL daily for 2 weeks. Quadriceps SM protein markers of fatty acid oxidation (FatOx), protein synthesis and protein catabolism were assessed.
RESULTS: CL increased relative lean mass in both sexes (P=0.012). In females, CL increased FatOx in WT, yet reduced FatOx in KO, while among males, CL reduced FatOx independent of genotype (P=0.04). Uncoupling protein 2 (UCP2) and fatty acid synthase (FASN) abundance were higher in females (P=0.004 and 0.037, respectively), and in both sexes, KO mice had higher SM UCP2 abundance (P=0.022). CL increased phosphorylated acetyl-CoA carboxylase (indicative of FatOx) in males, yet reduced it in females (P=0.015). Similarly, CL affected p706S kinase abundance (indicative of anabolic signaling) in a sexually dimorphic manner, increasing in males and decreasing in females. CL robustly increased SM FASN across sexes and genotypes (P<0.001).
CONCLUSION: CL increases SM FASN content, independent of sex and ERβ genomic activity. Further, novel sex-divergent effects of CL on SM metabolism were identified, some of which affected by loss of ERβ genomic activity.

Keywords:  Beta 3 adrenergic receptor agonist; anabolic; exercise mimetic; fat loss; fat oxidation; glucose metabolism

DOI:  https://doi.org/10.1530/JOE-25-0005